EP0155247B1 - A method for microphotometering microscope specimens - Google Patents

A method for microphotometering microscope specimens Download PDF

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Publication number
EP0155247B1
EP0155247B1 EP85850055A EP85850055A EP0155247B1 EP 0155247 B1 EP0155247 B1 EP 0155247B1 EP 85850055 A EP85850055 A EP 85850055A EP 85850055 A EP85850055 A EP 85850055A EP 0155247 B1 EP0155247 B1 EP 0155247B1
Authority
EP
European Patent Office
Prior art keywords
specimen
microscope
stepwise
light
effected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP85850055A
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German (de)
English (en)
French (fr)
Other versions
EP0155247A3 (en
EP0155247A2 (en
Inventor
Kjell Sture Carlsson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Integenx Acquisition Corp
Original Assignee
Molecular Dynamics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Application filed by Molecular Dynamics Inc filed Critical Molecular Dynamics Inc
Publication of EP0155247A2 publication Critical patent/EP0155247A2/en
Publication of EP0155247A3 publication Critical patent/EP0155247A3/en
Application granted granted Critical
Publication of EP0155247B1 publication Critical patent/EP0155247B1/en
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Classifications

    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/59—Transmissivity
    • G01N21/5907—Densitometers
    • G01N21/5911—Densitometers of the scanning type
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0096—Microscopes with photometer devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4738—Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474—Details of optical heads therefor, e.g. using optical fibres
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/10—Scanning
    • G01N2201/108—Miscellaneous
    • G01N2201/1087—Focussed scan beam, e.g. laser

Definitions

  • the invention relates to a method of microphotometry of a plurality of layers in a specimen, and of subsequent image processing, by the repetition of identical steps.
  • DE-A-2 665 525 discloses a method and an apparatus for increasing the range of depth of focus when optically imaging three-dimensional objects having different depth ranges corresponding to desired image levels wherein the object is focused through a plurality of levels to produce a plurality of images.
  • Each image is filtered with a high pass filter to suppress unfocused details and to pass sharp details.
  • the images are summed to produce a composite image containing only the sharp details passed by the filtering step.
  • the object of the present invention is to simplify and, in many instances, even to refine the methodology of effecting microscopic investigations, and at less cost.
  • the method according to the invention comprises producing a three-dimensional image of a volume of a microscope specimen (i.e. a specimen for microscopic study) taking a starting point from the method described in the introduction wherein the repeated identical steps each comprises the substeps of
  • the aforesaid measurement values together give a detailed description or picture of the whole of the volume determined through all of said plurality of parts.
  • Nerve cells exhibit an extremely large number of branches and present a complicated three-dimensional structure.
  • Investigatory studies of such structures with the aid of traditional microscope equipment are extremely difficult to carry out and are also very time-consuming.
  • the information obtained therefrom is incomplete.
  • Corresponding studies carried out in accordance with the invention have been found to provide abundantly more information than that obtained when carrying out the studies in accordance with known methods.
  • Other possible areas where the three-dimensional structure is of great interest include studies of the inner structures of cells, for example a study of the configuration of the cell core, chromosomes etc..
  • the illumination and registration technique according to the invention affords the following advantages. It is possible to select a thin section from the specimen for registration and to combine several such sections to produce a three-dimensional image.
  • the images are made richer in contrast and clearer by decreasing the level of stray light. Sensitive and delicate specimens are protected from harm, because the total light exposure is low.
  • the reference 10 identifies a microscope specimen through which there is laid an imaginary horizontal section comprising a plurality of part elements: for reasons relating to the technicalities of the drawing the section exhibits 20 rows in the x-direction and 15 rows in the y-direction, i.e. a total of 300 part elements, such as part elements 12 and 13 for example, but may in practice of course exhibit many more or far less elements and with sections of a different form, such as square or elongated rectangular sections for example, depending entirely upon the form of the specimen.
  • the specimen 20 illustrated in vertical sections in Fig. 2 constitutes part of a material surface to be studied.
  • a section 21, corresponding to the section 11 in Fig. 1, is placed in the upper part of the specimen and is thus here seen from the side.
  • the two indicated sections 11 and 21 are representative of what is referred to hereinafter as "the focal plane".
  • the apparatus illustrated in Fig. 3 includes a microscope 30 having an object table 301, a laser-light source 31 for producing a beam of light through a beam-splitting unit 32, and a scanner 33 operative in panning the beam of light to a plurality of locations in the focal plane (x-y-plane) of the microscope 30, an aperture 34, and a control and data-connection assembly 36 for controlling, inter alia, the scanner 33 via a line 361, and for collecting electric signals deriving from reflected and/or fluorescent light arriving at the detector 35 after having passed from the object table 301 through the microscope 30, the scanner 33 and the aperture 34, this light being converted in the detector 35 to electric signals which are transferred through the line 351 to the control assembly 36, and finally externally located equipment for storing, processing and visually displaying data originating from said signals, this equipment comprising a data processor 37 and an auxiliary store 38, and a display screen 39 connected to the data processor 37.
  • this equipment comprising a data processor 37 and an auxiliary store 38, and a display screen 39
  • a luminous dot or cursor created by the light beam from the laser source 31 is deflected by the scanner 33 to a number of positions in a specimen placed on the object table 301, in the focal plane, which focal plane may be the section indicated in Fig. 1.
  • Stray light possibly eminating from locations (volume elements) above, beneath or beside the location in the x-y-plane just scanned by the scanner 33, is excluded by the aperture 34 and is caused to deliver information relating to its characteristics through, for example, reflected light.
  • a control pulse is delivered from the control assembly 36 to the scanner 33, via the line 361, and the scanner therewith reflects the beam to the next location (e.g.
  • the object table 301 is thereupon moved stepwise (up or down) in response to a control pulse (signal) fed from the control assembly 35 to a drive unit 361 via the line 362, which drive unit guides directly movement of the table 301 in the z-direction.
  • the object table with the specimen thereon is thus displaced through a given distance in the z-direction, whereupon the focal plane of the microscope 30 will obtain a new position through the specimen, this new position being scanned in the same manner as that previously described.
  • the whole of the specimen is thus scanned in this way successively at equidistant locations along equidistant parallel lines in equidistant planes.
  • Signals are transferred from the scanner 33 and the drive unit 361 respectively to the control assembly 36, bearing information relating to the current position of the cursor created by the light beam (x-y-direction) and of the table 301 (z-direction).
  • the apparatus illustrated in Fig. 4 coincides with the apparatus illustrated in Fig. 3 with the exception that deflection caused through the scanner 43 is effected only in one direction (e.g. the y-direction), while the object table 401 is moved stepwise in the horizontal direction (x-direction) subsequent to the light beam having been advanced along a whole row or line and been displaced stepwise in a vertical direction (z-direction) subsequent to the light beam having been advanced along a whole section.
  • This modification may be suitable when studying specimens of substantially elongated rectangular shape.
  • circuits and devices illustrated in Figs. 3 and 4 correspond in the following manner:
  • the apparatus illustrated in Fig. 5 coincides with that illustrated in Fig. 3 with the exception that the scanner 33 is omitted totally and the object table 501 is instead arranged to be moved stepwise along a surface in the horizontal plane (x-y-plane) and stepwise in a vertical direction (z-direction). These movements are controlled from the drive unit 561 which receives, in turn, synchronizing pulses from the control assembly 56.
  • the apparatuses according to Figs. 3-5 are intended to utilize reflected and/or fluorescent light from the specimen. It is also possible to work with transmitted light, however, and the apparatus illustrated in Fig. 6 is intended for this case.
  • Light from the laser 61 passes the microscope 60 and is focused on a point in the focal plane in a specimen placed on the object table 601.
  • the light allowed to pass through or excited (fluorescence) by the specimen at the point in question is collected by an objective 602 and permitted to pass an aperture 64 and, in the case of fluorescence, a filter 603 to eliminate exiting laser light, whereupon detection is effected in the detector 65 (conversion to electric signals and analogue/ digital conversion) and collection in the control and data collecting assembly 66 in the aforedescribed manner.
  • the object table 601 is also caused to move stepwise, in response to control signals from the assembly 66, along a line or row in a surface plane (x-y-plane) and in a direction (z-direction) perpendicular to the surface plane.
  • the function of the apparatus is similar in other respects to the function of the previously described apparatus.
  • the invention is not restricted to the aforedescribed and illustrated embodiments.
  • the methods forming the basis for the apparatus illustrated in Figs. 3 and 4 see also the following claims 2 and 3, probably give optimal results in respect of reflected light, modifications can be made in principle for the use of transmitted light.
  • the drive units 361, 461 and 561 of respective apparatus according to Figs. 3-5 can also be used to advantage for controlling movement of the microscope objective in z-directions instead of respective object tables 301, 401 and 501. There is obtained in both instances (fixed objective, movable object table in z-direction; movable objective in z-directions, fixed object table in z-directions) a change in the mutual distance between the specimen 10 and the focal plane 11.
  • Fig. 7 illustrates schematically a specimen 10 through which sections 1-n have been laid (at right angles to the plane of the drawing) in accordance with the invention.
  • a researcher who during the course of his/her work finds that he needs to view a section through a given part of the specimen from a different angle, e.g. through sections 70-70, is able to immediately obtain from the measurement value equipment an image comprised of measuring results from a plurality of sections 1-n, and with a starting point from this view image can then find reason to concentrate his/her interest to another part of the specimen, perhaps along an additional section.
  • the possibilities are manifold and afford a high degree of flexibility in respect of research work.

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  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Microscoopes, Condenser (AREA)
  • Cameras Adapted For Combination With Other Photographic Or Optical Apparatuses (AREA)
EP85850055A 1984-03-15 1985-02-19 A method for microphotometering microscope specimens Expired - Lifetime EP0155247B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8401458 1984-03-15
SE8401458A SE455736B (sv) 1984-03-15 1984-03-15 Forfaringssett och anordning for mikrofotometrering och efterfoljande bildsammanstellning

Publications (3)

Publication Number Publication Date
EP0155247A2 EP0155247A2 (en) 1985-09-18
EP0155247A3 EP0155247A3 (en) 1988-06-08
EP0155247B1 true EP0155247B1 (en) 1991-06-05

Family

ID=20355166

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85850055A Expired - Lifetime EP0155247B1 (en) 1984-03-15 1985-02-19 A method for microphotometering microscope specimens

Country Status (7)

Country Link
US (2) US4631581A (enrdf_load_stackoverflow)
EP (1) EP0155247B1 (enrdf_load_stackoverflow)
JP (1) JPS60212716A (enrdf_load_stackoverflow)
CA (1) CA1228915A (enrdf_load_stackoverflow)
DD (1) DD244415A5 (enrdf_load_stackoverflow)
DE (2) DE3583050D1 (enrdf_load_stackoverflow)
SE (1) SE455736B (enrdf_load_stackoverflow)

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DD244415A5 (de) 1987-04-01
DE155247T1 (de) 1987-10-15
US4631581A (en) 1986-12-23
SE8401458D0 (sv) 1984-03-15
JPS60212716A (ja) 1985-10-25
CA1228915A (en) 1987-11-03
JPH0569210B2 (enrdf_load_stackoverflow) 1993-09-30
EP0155247A3 (en) 1988-06-08
DE3583050D1 (de) 1991-07-11
SE8401458L (sv) 1985-09-16
USRE34214E (en) 1993-04-06
EP0155247A2 (en) 1985-09-18

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